This project will investigate the role of the hippocampus and related medial temporal lobe (MTL) structures in[unreadable] sequence memory. These studies are guided by our recent findings with functional magetic resonance[unreadable] imaging (fMRI) indicating that the human hippocampus is activated in early stages of sequence learning[unreadable] (Schendan et a)., 2003), and also our recent animal and modeling studies that suggest the hippocampus is[unreadable] critical in memory for temporal order (Fortin et al., 2002), and for the disambiguation of overlapping[unreadable] sequences of events in memory (Sohal and Hasselmo, 1998; Agster et al., 2002). The proposed project has[unreadable] three specific aims. The first aim is to use fMRI to explore the scope of hippocampal involvement in[unreadable] sequence learning in humans. Experiments 1 and 2 will examine hippocampal, parahippocampal, prefrontal,[unreadable] and striatal activity during the encoding, delay, and retrieval components of encoding tasks that will contrast[unreadable] learning and memory performance for items, sequences of items, and spatial context information. These[unreadable] event-related fMRI studies directly parallel studies that have been and will be carried out in animal models.[unreadable] Our hypothesis is that the hippocampus is critical not only for associative and contextual learning, but also[unreadable] for remembering the order of events in unique experiences. We further predict that perirhinal activity will[unreadable] relate to item learning, but not contextual or sequence learning. The second aim is to use fMRI to explore the[unreadable] role of the hippocampus in sequence disambiguation. Experiments directly parallel studies in animal models[unreadable] (Agster et al., 2002; Wood, et al, 2000). Exp. 3 will examine hippocampal activation in encoding overlapping[unreadable] versus non-overlapping non-spatial sequences. Exp. 4 is the spatial analog of Exp. 3, and will examine[unreadable] navigation through virtual reality mazes using overlapping and non-overlapping paths. The third aim is to[unreadable] use fMRI to contrast the medial temporal lobe, prefrontal, and striatal systems in sequence learning. Exp. 5[unreadable] examines implicit sequence learning in a sequence embedded in a "prefrontal" N-back task. Exp. 6[unreadable] examines learning of first order (FOG) or second order conditional (SOC) sequences in an incidental picture[unreadable] encoding task. The prediction is that FOG sequences will activate the striatum but not the MTL, whereas[unreadable] SOC sequences will activate the MTL. The combined studies will provide a hypothesis-driven examination of[unreadable] episodic sequence learning that closely parallels the studies and models proposed.